Tight skin (Tsk) is an autosomal dominant mutation which occurred spontaneously in the inbred mouse strain B10.D2(58N)/Sn; the original mutant was detected because it displayed unusually tight skin in the interscapular region (Green, M. C., et al. (1976). Am. J. Pathol. 82, 493-511.). Heterozygous Tsk mice have thickened skin which is firmly bound to the subcutaneous and deep muscular tissues and which lacks the pliability and elasticity characteristic of normal skin. Excessive accumulation of several collagens and glycosaminoglycans occurs in various organs including the skin, heart, and lungs (reviewed in Jimenez and Christner, (1994). Clinics Derm. 12, 425-436.). The Tsk mutation also results in larger skeletal size apparently caused by excessive growth of bone and cartilage. Homozygous Tsk/Tsk embryos degenerate in utero at .about.8 days of gestation, whereas Tsk heterozygotes have a normal life span.
The Tsk mouse has been useful as a model for several human diseases. The increased expression of several collagen types found in the enlarged heart make Tsk/+ mice valuable models for the study of myocardial hypertrophy (Osborn, T. G., et al. (1987). J. Biol. Cell. Cardiol. 19, 581-587; Chapman, D., Eghbali, M. (1990). Cardiovas. Res. 24, 578-583; Bahey, R. I., et al. (1993) Cardiovas. Res. 27, 1061-1065). Heterozygous Tsk/+ mice serve as a model for human hereditary emphysema (Szapiel, S. V., et al. (1981). Amer. Rev. Respir. Dis. 123, 680-685; Rossi, G. A. et al. (1984) Amer. Rev. Respir. Dis. 129, 850-855; Gardi, C., et al. (1989). Exp. Mol. Pathol. 50, 398-410; Martorana, P. A., et al. (1989). Am. Rev. Respir. Dis. 139, 226-232). Tsk/+ mice have also been proposed as models for the hereditary connective tissue disorder, congenital fascial dystrophy, because the thickened fascia found in these patients resembles the subdermal thickening seen in Tsk/+ mice (Jablonska, S., et al. (1989). J. Am. Acad. Derm. 21, 943-950).
Another major interest in the Tsk mouse is that it has provided an animal model for the human disease Systemic Sclerosis or scleroderma (SSc). SSc is a connective tissue disease characterized by excessive extracellular matrix deposition in skin and various internal organs. It is generally accepted that SSc is an acquired disease, although a few instances of familial inheritance have been reported. The frequently progressive tissue fibrosis is largely responsible for the morbidity and mortality of patients with SSc. Although several animal models exist for the study of SSc, no one model reproduces all the features of the human disease. The effects of the Tsk mutation mimic the excessive accumulation of collagen in the dermis and some internal organ observed in patients with SSc. These abnormalities result from increased biosynthesis of collagen by Tsk fibroblasts. The Tsk mutation thus provides a unique opportunity to investigate the pathogenesis of tissue fibrosis at the molecular level.
There remains a need to discover the molecular nature of Tsk. There remains a need for methods of identifying individuals who have the genetic disorder associated with Tsk.